Despite the obvious costs to individuals and society and importance for health, we know relatively little about the etiology of risk-taking behaviors. Progress toward understanding the genetic and environmental factors influencing the propensity to engage in self-harm, violence and sensation seeking behaviors will be hastened by the availability of a genomically tractable animal model. Our long term goal is to develop stickleback fish (Gasterosteus aculeatus) as a model system to understand how genes interact with the environment to influence behaviors. The overall objective of this application is to identify and test candidate genes and pathways underlying natural variation in risk-taking behaviors. Our central hypothesis is that there are inherited and environmentally-responsive genes that affect risk-taking behaviors in sticklebacks, and those genes are shared with other animals, including humans. The rationale that underlies the proposed research is that an unbiased approach to studying natural variation in the propensity to engage in risk-taking behaviors which are both genetically based and environmentally-sensitive is likely to identify candidate genes that are relevant to human health. Identification of the genes pathways underlying risk-taking behaviors will contribute to the NIH mission to improve the health of the nation by aiding psychopharmacological efforts for the treatment and diagnosis of externalizing disorders in humans. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Identify genes associated with differences in risk- taking behaviors between individuals and populations; 2) Identify genes underlying risk-taking behaviors that are responsive to adverse environmental conditions; 3) Test candidate genes related to risk-taking behaviors in replicated populations. Under Aim 1, the gene expression profiles of risk-prone versus risk-averse individuals will be compared using whole-genome expression microarrays. Under the second Aim, the behavior and gene expression of individuals that are exposed to stressful environments will be compared against unstressed conspecifics. The two stressors are absence of parental care, which has an important effect on risk-taking behaviors in this species, and exposure to predators during development. Under Aim 3, the genes that are good candidates from Aims 1 and 2 will be tested in independent, replicate populations. This timely project capitalizes on the availability of new genomic information for an organism with a well-described and fascinating behavioral repertoire that until recently has been exempt from molecular dissection. The key innovation of this work is that it takes advantage of genetic and environmental sources of variation to identify candidate genes and uses the unique evolutionary history of sticklebacks to test a biomedically-relevant hypothesis in a replicated manner. The proposed studies use a new animal model to address fundamental questions about the origin of behaviors that have adverse consequences for health. The studies have potential application to understanding the etiology of human psychopathology. The proposed research has relevance to public health, because it will suggest candidate genes and pathways for the diagnosis and treatment of behavioral disorders in humans.